Systemic mastocytosis in adults: 2011 update on diagnosis, risk stratification, and management

Abstract

Disease overview: Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MC) in one or more extracutaneous organs. Diagnosis: The major criterion is presence of multifocal clusters of morphologically abnormal MC in the bone marrow. Minor diagnostic criteria include elevated serum tryptase level, abnormal MC expression of CD25 and/or CD2, and presence of KITD816V. Risk stratification: The prognostic relevance of the 2008 World Health Organization (WHO) classification of SM has recently been confirmed. Classification of SM patients into indolent (SM), aggressive SM (ASM), SM associated with a clonal non‐MC lineage disease (SM‐AHNMD), and mast cell leukemia (MCL) subgroups is a useful first step in establishing prognosis. Risk‐adapted therapy: SM treatment is generally palliative. ISM patients have a normal life expectancy and receive symptom‐directed therapy; infrequently, cytoreductive therapy may be indicated for refractory symptoms. ASM patients have disease‐related organ dysfunction; interferon‐α (±corticosteroids) can control dermatological, hematological, gastrointestinal, skeletal, and mediator‐release symptoms, but is hampered by poor tolerability. Similarly, cladribine has broad therapeutic activity, with particular utility when rapid MC debulking is indicated; the main toxicity is myelosuppression. Imatinib has a therapeutic role in the presence of an imatinib‐sensitive KIT mutation or in KITD816‐unmutated patients. Treatment of SM‐AHNMD is governed primarily by the non‐MC neoplasm; hydroxyurea has modest utility in this setting. Dasatinib's in vitro anti‐ KITD816V activity has not translated into significant therapeutic activity in most SM patients. In contrast, preliminary data suggest that Midostaurin may produce significant decreases in MC burden in some patients. Am. J. Hematol. 86:363–371, 2011. © 2011 Wiley‐Liss, Inc.

World Health Organization Classification, Evaluation, and Genetics of the Myeloproliferative Neoplasm Variants

“…Less frequent mutations include JAK2 V617 and N-RAS. 22 if rearranged PDGFRA is present, the case should be classified according to the genetic defect. 23 …”

“…22 The mast cells of most patients with SM carry KIT D816V, but its detection in clinical samples reportedly may vary from 50%-95% depending on the number of mast cells in the specimen and the sensitivity of the assay. [22][23][24][25] Nearly 30% of patients with SM demonstrate mutated TET2, with or without demonstrably mutated KIT. Although mutated TET2 has been associated with monocytosis in SM, the mutation carries no proven prognostic influence and is not at all specific, because it is observed in other MPN and MDS/MPN entities.…”

“…21 The genetic abnormality most frequently associated with SM is the gain-of-function mutation KIT D816V. 22 The mast cells of most patients with SM carry KIT D816V, but its detection in clinical samples reportedly may vary from 50%-95% depending on the number of mast cells in the specimen and the sensitivity of the assay. [22][23][24][25] Nearly 30% of patients with SM demonstrate mutated TET2, with or without demonstrably mutated KIT.…”

“…Although mutated TET2 has been associated with monocytosis in SM, the mutation carries no proven prognostic influence and is not at all specific, because it is observed in other MPN and MDS/MPN entities. 22,23 Cases of SM associated with eosinophilia should be investigated for PDGFRA rearrangement; such cases are not associated with mutated TET2 or KIT, and There is a clonal cytogenetic or molecular genetic abnormality or blast cells are Ͼ 2% in the peripheral blood or Ͼ 5% in the BM *Cytogenetics: none specific, reported abnormalities include trisomy 8, t(10; 11)(p14q21), t(7;12)(q11;p11). 1 Cases with t(8;9)(p22;p24);PCM1-JAK2 likely will fall into this category.…”

Diagnosis and treatment of mast cell disorders: practical recommendations

“…25 In the presence of peripheral blood eosinophilia (> 1500 cells/ ml), investigation of the CHIC-2 deletion and FIP1L1-PDGFRA rearrangement by means of fluorescence in situ hybridization or the reverse transcriptase polymerase chain reaction is indicated. 1,5,40,43 Moreover, detection of translocations in regions containing chromosome bands 5q31-5q33 via conventional cytogenetic analysis generally enables identification of cases associated with the PDGFRB rearrangement. 43,44 Cases that have either a PDGFRA or PDGFRB mutation associated with mast cell hyperplasia should be properly classified as "myeloid neoplasms with PDGFRA or PDGFRB rearrangements, " according to the World Health Organization's classification system.…”